Transfer of IL-1Ra cDNA to Osteoarthritic Knee

描述(由申请人提供)：将IL-1ra基因转移到关节的滑膜衬里，在类风湿性关节炎和骨性关节炎的动物模型中显示出安全性和有效性。一期研究被提议评估局部体内基因转移对骨性关节炎关节的适用性，这是这种类型基因治疗的极好候选者。在该方案中，通过体内基因转移将IL-1ra基因转移到9例膝骨性关节炎患者的膝关节。一种重组的、血清2型的腺相关病毒(AAV.IL-1ra)将用于此目的，其转基因表达由人巨细胞病毒即刻早期启动子驱动。临床级AAV.IL-1ra将由国家基因载体实验室生产。以剂量递增的方式，在全膝关节置换手术前12周，3名受试者分别在一个膝关节内注射5x1011(低剂量)、5x1012(中剂量)或5x1013(高剂量)病毒颗粒。在注射病毒之前和关节置换手术之前，将立即从膝关节抽出滑液，并抽出外周血。关节内转基因表达将通过测量滑液中IL-1ra的浓度来评估。还将测量外周血中IL-1ra的浓度。在关节置换手术中恢复的关节组织将被检查是否存在整合的和外体的病毒基因组，以及转基因表达。可能发生的不良关节内事件将在病毒注射前和关节置换手术前立即通过关节磁共振成像进行评估。将通过分析在注射病毒前、关节置换手术前以及关节置换手术后3、6和12个月抽取的外周血液样本来收集额外的安全信息。如果该方案能够以安全和有效的方式在关节内产生相应水平的IL-1ra转基因表达，它将为随后的介入研究确定对骨关节炎的疗效奠定基础。

DESCRIPTION (provided by applicant): Transfer of IL-1Ra cDNA to the synovial linings of joints has shown both safety and efficacy in animal models of rheumatoid- and osteo-arthritis. A phase I study is proposed to assess applicability of local, in vivo gene transfer to joints with osteoarthritis, an excellent candidate for this type of gene therapy. In this protocol IL-1Ra cDNA will be delivered by in vivo gene transfer to the knee joints of 9 subjects with osteoarthritis of the knee. A recombinant, serotype 2, adeno-associated virus (AAV.IL-1Ra) will be used for this purpose, with transgene expression driven by the human cytomegalovirus immediate-early promoter. Clinical grade AAV.IL-1Ra will be produced by the National Gene Vector Laboratory. In a dose-escalation manner, 3 subjects will each receive 5x1011 (low dose), 5x1012 (middle dose) or 5x1013 (high dose) viral particles in one knee joint, twelve weeks before total knee joint replacement surgery. Synovial fluid will be aspirated from the knee joints, and peripheral blood withdrawn, immediately before injection of the virus, and again immediately before joint replacement surgery. Intraarticular transgene expression will be assessed by measuring the IL- 1Ra concentration of the synovial fluid. IL-1Ra concentrations in peripheral blood will also be measured. Articular tissues recovered at the time of joint replacement surgery will be examined for the presence of integrated and episomal viral genomes, and for transgene expression. Possible adverse intraarticular events will be evaluated by MR imaging of joints immediately before viral delivery and immediately before joint replacement surgery. Additional safety information will be gathered by analysis of peripheral blood samples drawn immediately before injection of virus, immediately before joint replacement surgery, and 3, 6 and 12 months after joint replacement surgery. If this protocol is able to generate relevant levels of intraarticular IL-1Ra transgene expression in a safe and efficient manner, it will set the stage for a subsequent interventional study to determine efficacy in osteoarthritis.